Project Summary Per- and polyfluoroalkyl substances (PFAS) are pervasive in everyday life. Their extensive use in consumer products, industrial processes and fire-fighting foam has led to significant contamination of drinking water and food resulting in universal human exposure. While many studies have investigated the disruption of lipid metabolism and immune system function by PFAS, less attention has been paid to the adverse effects of PFAS on bone health. In light of the epidemiological associations between PFAS and lower bone density in children and adults and the lack of studies investigating the causality and/or mechanisms by which PFAS could interfere with bone metabolism, the objective of this study is to begin to define the effects of perfluorooctanoic acid (PFOA) on bone quality. Our research focuses on the interaction of PFAS with nuclear receptors, a likely mechanism through which PFAS could perturb bone cell function. We have developed a novel, human-relevant model in which to study the adverse health effects of PFAS: mice expressing human peroxisome proliferator activated receptor α (PPARα) fed a diet based on the What We Eat In America analysis in NHANES. Our working hypothesis is that PFAS reduce bone quality through their interaction with nuclear receptors in multiple bone cell types. To generate the preliminary data needed to support the proof-of-principle for an association between PFAS exposure and bone health and to hone our working hypothesis, we propose the following specific aim. We will define the effect of long term PFOA exposure on cortical and trabecular structure, osteoblast and osteoclast number and function, and the bone transcriptome. We propose to take advantage of bone and serum samples collected from experiments already conducted in humanized PPARα mice, PPARα null mice and PPARα wildtype mice: Study 1 – young female and male mice, fed an adolescent American diet, exposed to PFOA in drinking water for 6 weeks and Study 2 – adult female and male mice, fed an adult American diet exposed to PFOA in drinking water for 14 weeks. Biological effects on liver and serum lipid homeostasis are evident in these mice, which have serum PFOA concentrations similar to occupationally exposed people. Bone structural, histological, biochemical and transcriptomic data will be analyzed. Comparison between genotypes will begin to define the contribution of PPARα in PFAS-induced adverse effects on bone quality. The results of this research will provide essential new data on how PFAS negatively impact bone health and provide the needed foundation to begin to address a critical gap in PFAS research, establishing the potential for causality in associations between PFAS and loss of bone quality in humans.

Project Narrative People are exposed to per- and polyfluoroalkyl substances daily from multiple sources. Epidemiological studies show an association between serum PFAS concentrations and lower bone density in both children and adults. Here, we investigate a new in vivo model to study the mechanism through which PFAS impair bone health.